Morbidity and mortality from septic shock have been related to the magnitude of the inflammatory response elicited early in the disease. How the magnitude of this response is regulated is poorly understood. Underlying viral infection has been associated with enhanced mortality from secondary bacterial infection. While some viral infections induce anergy-increasing susceptibility to bacterial infection, this proposal will focus on early viral stimulated induction of IFNalpha/beta which potentiates inflammatory cytokine responses and diminishes microbicidal function leading to decreased survival. Sensitization to bacterial challenge can also be induced by exogenous dsRNA mimicking dsRNA produced during viral replication. DsRNA can activate cells by signaling through the TLR3 pathway, activating both the TRIF and MyD88 pathways leading to the induction of IFNalpha/beta, activation of dsRNA protein kinase (PKR) and elF2alpha leading to inhibition of translation as occurs in early in viral infection. Although this pathway is well characterized, where and how it alters responsiveness in the anti-bacterial pathways to cause a potentiated cytokine response while inhibiting microbicidal activity is not known. Our hypothesis is that the induction and actions of IFNalpha/beta early in the host response to viral infection, can lead to exaggerated cytokine responses and impaired microbicidal activity thereby contributing to the morbidity and mortality from septic shock. To examine this the following specific aims are proposed: 1) To characterize the phenotype and function of a """"""""primed"""""""" peritoneal macrophage under the influence of simulated early viral infection. 2) To determine which signaling pathways were necessary for creating """"""""primed"""""""" conditions in the peritoneal macrophage to subsequent challenges. 3) To determine whether other well-known priming strategies employ pathways common to early viral infection and to determine if simulated early viral infection leads to priming for other aseptic inflammatory stimuli. Investigating the impact of viral infection on immune responsiveness may further the understanding of critical determinants of morbidity seen during infection ranging from localized infection to fulminant septic shock. Certainly it promises to extend the understanding of individual variability to septic challenges and may provide insight into therapeutic possibilities for inflammatory entities such as septic shock.
| Doughty, Lesley A; Carlton, Stacey; Galen, Benjamin et al. (2006) Activation of common antiviral pathways can potentiate inflammatory responses to septic shock. Shock 26:187-94 |
